PROJECT SUMMARY/ ABSTRACT Chronic drug use is associated with low levels of dopamine release in the striatum. Despite the importance to translational science, the developmental course of low dopamine function is unknown. For instance, it is fundamentally unclear in humans whether low dopamine function precedes or follows from substance use, if rate of divergence in substance-exposed youth is slow or rapid, or if there are differential effects by gender or by pattern of substance use. The primary obstacles are that 1.) Positron Emission Tomography (PET) imaging cannot be utilized in pediatric populations to track early changes in dopamine function, and 2.) there is no developmentally-appropriate alternative imaging method. Translational science awaits a valid index of a dopamine-related biosynthesis pathway for assessing normal developmental trajectories in youth, as well as deviation before, during, and after onset of substance use. Recently, we found that a neuromelanin-sensitive magnetic resonance imaging (NM-MRI) sequence yields a direct index of dopamine release in the striatum. Unlike PET imaging, NM-MRI does not involve radiation exposure and is appropriate for pediatric populations. We have also observed that NM-MRI signal is detected as early as 11 years of age. This R21 application proposes to collect NM-MRI in 160 20-22 year-olds, an age group that is transitioning from adolescence to adulthood. Our aim is to establish a definitive link between NM-MRI level and total lifetime substance use. Total lifetime substance use will be carefully assessed by semi-structured interview and quantified dimensionally using factor analysis. We will also explore gender differences and identify if specific aspects of substance use differentially impact NM-MRI level over and above total exposure (e.g., age of onset). The women will be recruited from an existing cohort allowing us to test the link using prospective (archival), as well as retrospective (newly collected), substance use data. The men will be newly recruited and allow for a test of gender differences. Positive results will be novel evidence of a link between early-course dopaminergic disturbance and adolescent-onset substance use. This would support use of NM- MRI to describe synergistic links between dopamine function and adolescent substance use prospectively in a new pediatric study. Indeed, NM-MRI is a promising new tool for dopamine research where PET imaging is not feasible due cost, access to facilities, health risk, or age of sample.